Alkylaminopyridoguanamines



United States Pat ALKYLAMINOPYRIDOGUANAMINES Seymour L. Shapiro, Hastings-on-Hudson, and Louis Freedman, Bronxville, N.Y., assignors to U.S. Vitamin Corporation, New York, N.Y., a corporation of Delaware No Drawing. Application December 3, 1958 Serial No. 777,854

4 Claims. 01. zoo-249.9

This invention is concerned with ring pyridylated guanamines, and specifically with pyridylguanamines having alkylamino groups which may be represented by the following formula LNH.

wherein R is alkyl having a carbon content C -C and may be substituted or unsubstituted, and saturated and unsaturated, cycloalkyl having a carbon content of C -C and arylalkyl having a carbon contentC- C R is .hy-

drogen or methyl, and those structures where R plus R are joined directly or through an oxygen atom to give polymethylene or oxaalkylene radicals having a carbon content C -C and Py is selected from the group consisting of S-pyridyl and 4-pyridy1.

The compounds of this invention show broad spectrum pharmacological effects including utility as hypotensive agents, central nervous system depressants, analgesicsand anti-inflammatory agents.

The compounds of this invention are conveniently prescribed in Table I.

2,937,170 Patented May 17, 1960 The ring pyridylated guanamines herein described are weak bases, and can form salts with the mineral acids such as hydrochloric, hydrobromic, sulfuric acids and the like.

The biguanides which-are required as intermediate reactants may be obtained by fusion of the amine hydrochloride R R NH.HC1 with dicyandiamide following published procedures (Shapiro et al., J. Am. Pharm. Assoc., Sci. Ed, 46, 679 (1 957); Shapiro et al., J. Am. Chem. Soc.,79, 5064 (1957)).

Typical compounds'prepared' in this invention are de- BG3H5=811YL Q N (GH2)5-Wll2h attached nitrogen gives a piperidyl group.

C H11=eyelohexyL When evaluated by accepted pharmacological procedures, the following useful properties of the compounds of this invention have been noted and have been summarized in Table II.

' TABLE II Pharmacologzcal propertzes of compounds No.- LDmin. Pharmacological Quantitation of I Reference to Procedure Used Response Response 1 4B... Shapiro et al., J. Am. Chem. Soc, 80,

2743 (1958). 4-0.-.- Do. 3-13.--. .-do Do. 4-0.--. 250 Central nervous system Shapn-o et al., J. Am. Chem. 800., 80,

5 depression. 1648 (1958). 4-13-..- 250 do Do. .3-C 750 49% 20 mgJkg- Dp.

3E 400 .Ann inflammatorylounitslgram Shapiro et al., J. Am. Pharm. Assoc,

. Sci. Ed., 46, 333 (1957). 4-15...- 100 Analgesic 33% 75 mgJkg Bizagnflilig 05 al., Brit. J. PharmacoL, 9,

' 5 4-F 1,000 -do 83% 330 mgJkg Do. 3-18---- 300 Antihistamine Inhibits histamine Shapiro et al., I. Am. Pharm. Assoc,

Sci. Ed., 46, 333 (1957).

B The number used corresponds to that indicated in Table I. b The LDmin is the minimum lethal dose, in mg./kg. as established in subcutaneous tests in mice.

pared by reaction in an alcoholic solution of the appropriately substituted biguanide with the ester of the pyridine carboxylic acid, as for example, ethyl nicotinate, or

methyl isonicotinate according to the following equation NH NH I N Sodium methoxide is desirably added as a catalyst. After a suitable reaction period, generally 24-96 hours at 20 C., the reaction is quenched by dilution with water and the product recovered by filtration.

EXAMPLE 1 2-allylamin0-4-amin0-6- (3-pyridyl) -s-triazine. A solution of 8.9 g. (0.05 mole) of allylbiguanide hydrochloride in 50 ml. of methanol was treated with 22 ml. (0.1 mole) of 25% sodium methoxide in methanol cooled to 0 C. and a 7.6 g. (0.05 mole) portion of ethyl nicotinate added. After 72 hours at 20 C. the reaction mixture 3 was diluted with 150 ml. of water and after 72 hours the roduct (6.2 g.) was separated and recrystallized (acetonitrile), melting at 148149 C.

Analysis.Calcd. for C H N C, 57.9; H, 5.3 N, 36.8. 'Found: C, 58.3; H, 4.8; N, 37.2.

The product was identified further by the preparation of its picrate which melted at 220 C. (propanol).

Analysis.Calcd. for C17H15N907: C, 44.6; H, 3.3; N, 27.6. Found: C, 44.6; H, 3.0; N, 27.6.

EXAMPLE 2 2 -amz'n0-4-a'imethyZamina-6-(3-pyridyl) s triazirm- Following the procedure of Example 1, and employing N,N-dimethylbiguanide hydrochloride, the product (5.8 g.) was obtained from a 0.05 mole run, and upon recrystallization (ethanol) melted at 200202 C.

Analysis.Calcd. for C H N C, 55.5; H, 5.6; N, 38.9. Found: C, 55.5; H, 6.1;,N, 38.8.

In a similar manner, using N-methyl-N'-benzylbiguanide hydrochloride, the product 2-amino-4(N-methylbenzylarnino)-6-(3-pyridyl)-s-triazine may be obtained.

EXAMPLE 3 2-amino-4-is0amylamino-6-(3-pyridyl) s triazin'e. Following the procedure of Example 1, and employing is'oamylbiguanide nitrate, the product (5.6 g.) was obtained from a 0.034 mole run, and upon recrystallization (acetonitrile), melted at 120123 C.

Analysis.-Calcd. for C H N C, 60.4; H, 7.0; N, 32.5. Found: C, 60.3; H, 7.0; N, 32.6.

In a similar manner, using n-butylbiguanide nitrate, the product 2-amino-4-(n-butylamino)-6-(3-pyridyl)-striazine may be obtained.

EXAMPLE 4 2-amino-4-(1 -piperidino)-6-(3 pyridyl) s triazine.- Following the procedure of Example 1, and employing N,N-pentamethylenebiguanide hydrochloride, the product (4.4 g.) was obtained from a 0.026 mole run and upon recrystallization (acetonitrile), melted at 164-166 C.

AnaIysis.-Calcd. for C H N C, 60.9;H, 6.3; N, 32.8. Found: C, 60.8; H, 6.4; N, 32.8. V

In a similar manner using the biguanide derived from morpholine, the product 2-amino-4-(4-morpholino) -6-(3- pyridyl)-s-triazine may be obtained.

EXAMPLEB 2-zzmin0-4-cycl0hexylamin0-6-(3-pyridyl) s-triazine.

Following the procedure of Example 1, andemploying cyclohexyl biguanide, the product (8.5 g.) was obtainedfrom a 0.05 mole run and upon recrystallization (acetoni- W p 7 guanide hydrochloride in 45 ml. of methanol was treated.

with 20 ml. (0.08 mole) of 25% sodium methoxide in methanol, cooled to 0 C. and 5.5 g. (0.04 mole) of methyl isonicotinate added. After storage at 20 C. for 5 days, the reaction was diluted with ml. of water and after standing 24 hours, the product (7.2 g.) which separated was recrystallized (ethanol), melting at 173- 174 C.

Analysis.Calcd. for cleHlfiNfi: C, 65.7; H, 5.5; N, 28.8. Found; C, 65.5; H, 5.8; N, 29.0.

In a similar manner using benzylbiguanide, hydrochloride, the product 2-amino-4-benzylamino-6-(4-pyridyl)-striazine may be obtained.

EXAMPLE 7 2 -allylam in0-4-amin0-6- (4-pyridyl -s-triazine.-Following the procedure of Example 6, andemploying allylbiguanide hydrochloride, the product (6.8 g.) was obtained from a 0.05 mole run, and upon recrystallization (acetonitrile) melted at l50152 C.

Analysis.Calcd. for C H N C, 57.9; H, 5.3; N, 36.8. Found: C, 58.0; H, 4.9; N, 37.3.

EXAMPLE 8 V Z-amino-4-is0amylamino-6-(4 pyridyl) s triaz0ne.

Following the procedure of Example 6, and employing isoamylbiguanide nitrate, the product (5.5 g.) was obtained in a 0.034 mole run and upon recrystallization (acetonitrile), melted at 156 C.

Analysis.Calcd. for C H N C, 60.4; H, 7.0; N, 32.5. Found: C, 60.1; H, 6.8; N, 33.2.

In a similar manner using n-amylbiguanide hydrochloride, Z-amino-4-(n-amylamino) -6-(4-pyridyl) -s-triazine may be obtained.

The novel compounds of this invention can be combined with solid or liquid pharmaceutical carriers forformulated into the form of tablets, powder packets or capsules, or, dissolved in suitable solvents for oral and parenteral administration for human or veterinary use.

It is to be understood that itv is intended to cover all changes and modifications of the examples of the invention herein chosen for the purpose of illustration which do not constitute departure from the spirit and scope of the invention.

We claim:

, 1. 2-amino-4-isoamylamino-6- 3-pyridyl) -s-triazine.

2. 2-amino-4-cyclohexylamino-6- 3-pyridyl) -s-triazine.

3. 2-amino-4-(,B-phenethylamino) -6-(4-pyri dyl)-s triazine.

4, 2-amino-4-isoamylamino-6-(4-pyridyl) s-triazine.

References Cited in the file of this patent UNITED STATES PATENTS Thurston et a1 Dec. 26, 1950 OTHER REFERENCES 7 Detweiler et al.: Journal of the American Chemical Society, vol. 74, pages 1483 to 1485 (1952). 

1. 2-AMINO-4-ISOAMYLAMINO-6-(3-PYRIDYL)-S-TRIAZINE. 